Tuberculosis (TB) infection is the leading cause of death in the setting of the Acquired Immune Deficiency Syndrome (AIDS). In the human immunodeficiency virus-1 (HIV-1)/TB co-infected host, the pathogenesis and outcome of each infection is greatly influenced by the other. Of the at least 11 subtypes or clades of the major (M) group of HIV-1 strains responsible for the current pandemic, the original clade or subtype isolated, B, has been the most studied. The C and E subtypes, however, are currently the most prevalent globally, accounting for approximately 50% and 30% of all new infections, respectively, and are the most prevalent in those areas of the world also most heavily burdened with TB, Africa and Asia. Notably, there are molecular differences between the B, C, and E subtypes, including distinct long terminal repeat (LTR) and transactivator of transcription (Tat) protein sequences, which are crucial for HIV-1 gene expression, replication, transmission, and disease progression, and it has been suggested that these differences may account for the disproportionate spread of subtypes C and E. Different clinical isolates of the causative agent of TB, Mycobacterium tuberculosis, (MTb), also have different phenotypes with respect to their ability to infect, cause disease and elicit cytokine responses including different levels of the cytokine tumor necrosis factor (TNF), which is involved in both the containment of TB disease in the latently infected host and in stimulating HIV-1 replication. Thus, characterization of the regulation of distinct HIV-1 subtypes and their interaction with MTb and differential host production of TNF is critical to the understanding of the pathogenesis of co-infection and to understanding the spread of the C and E HIV-1 subtypes. Our hypothesis, to be tested in Aims 1 and 2, is that LTR-mediated HIV-1 transcription is regulated by MTb in a subtype-specific manner via the recruitment of distinct sets of cellular activators and the remodeling of the LTR chromatin environment in the distinct subtypes. In Aim 3, we will test the hypothesis that subtype specific Tat proteins and diverse MTb clinical strains modulate TNF levels and have distinct effects on the transcription of the HIV-1 B, C and E LTRs. We anticipate that this proposal will result in contributionsto our understanding of the basic mechanisms involved in subtype specific HIV-1 replication by MTb and provide insight into TAT and MTb strain variation upon both HIV-1 and TNF regulation. We also expect that these studies may shed light on why the C clade of HIV-1 is expanding so rapidly in countries with a high TB burden. The long range goal of these studies is to identify subtype-specific transcriptional targets to inhibit HIV-1 replication in the setting of MTb infection and/or T cell activation secondary to MTb specific host immune responses.